The present disclosure relates to treatments for dysregulated production of blood cellular components, including red blood cells, neutrophils, and platelets. Hematopoiesis is the formation of cellular components of the blood from self-renewing hematopoietic stem cells located mainly in the bone marrow, spleen, or lymph nodes during postnatal life. Blood cells can be classified as belonging to the lymphocytic lineage, myelocytic lineage, or erythroid lineage. By a process known as lymphopoiesis, common lymphoid progenitor cells give rise to T-cells, B-cells, natural killer cells, and dendritic cells. By a process termed myelopoiesis, common myeloid progenitor cells give rise to macrophages, granulocytes (basophils, neutrophils, eosinophils, and mast cells), and thrombocytes (platelets). Finally, by a process known as erythropoiesis, erythroid progenitor cells give rise to red blood cells (RBC, erythrocytes).
Postnatal erythropoiesis occurs primarily in the bone marrow and in the red pulp of the spleen. The coordinated action of various signaling pathways controls the balance of cell proliferation, differentiation, survival, and death. Under normal conditions, red blood cells are produced at a rate that maintains a constant red cell mass in the body, and production may increase or decrease in response to various stimuli, including increased or decreased oxygen tension or tissue demand. The process of erythropoiesis begins with the formation of lineage-committed precursor cells and proceeds through a series of distinct precursor cell types. The final stages of erythropoiesis occur as reticulocytes are released into the bloodstream and lose their mitochondria and ribosomes while assuming the morphology of mature red blood cell. An elevated level of reticulocytes, or an elevated reticulocyte:erythrocyte ratio, in the blood is indicative of increased red blood cell production rates. The mature red blood cell (RBC) is responsible for oxygen transport in the circulatory systems of vertebrates. Red blood cells contain high concentrations of hemoglobin, a protein that binds to oxygen in the lungs at relatively high partial pressure of oxygen (pO2) and delivers oxygen to areas of the body with relatively low pO2.
Erythropoietin (EPO) is widely recognized as a significant positive regulator of postnatal erythropoiesis in vertebrates. EPO regulates the compensatory erythropoietic response to reduced tissue oxygen tension (hypoxia) and low red blood cell levels or low hemoglobin levels. In humans, elevated EPO levels promote red blood cell formation by stimulating the generation of erythroid progenitors in the bone marrow and spleen. In the mouse, EPO enhances erythropoiesis primarily in the spleen.
Effects of EPO are mediated by a cell-surface receptor belonging to the cytokine receptor superfamily. The human EPO receptor gene encodes a 483 amino acid transmembrane protein; however, the active EPO receptor is thought to exist as a multimeric complex even in the absence of ligand (see, e.g., U.S. Pat. No. 6,319,499). The cloned full-length EPO receptor expressed in mammalian cells binds EPO with an affinity similar to that of the native receptor on erythroid progenitor cells. Binding of EPO to its receptor causes a conformational change resulting in receptor activation and biological effects including increased proliferation of immature erythroblasts, increased differentiation of immature erythroblasts, and decreased apoptosis in erythroid progenitor cells [see, e.g., Liboi et al. (1993) Proc Natl Acad Sci USA 90:11351-11355; Koury et al. (1990) Science 248:378-381].
Various forms of recombinant EPO are used by physicians to increase red blood cell levels in a variety of clinical settings, particularly in the treatment of anemia. Anemia is a broadly-defined condition characterized by lower than normal levels of hemoglobin or red blood cells in the blood. In some instances, anemia is caused by a primary disorder in the production or survival of red blood cells (e.g., myelodysplastic syndromes). More commonly, anemia is secondary to diseases of other systems [see, e.g., Weatherall & Provan (2000) Lancet 355, 1169-1175]. Anemia may result from a reduced rate of production or increased rate of destruction of red blood cells or by loss of red blood cells due to bleeding. Anemia may result from a variety of disorders that include, for example, acute or chronic renal failure or end stage renal disease, chemotherapy treatment, a myelodysplastic syndrome, rheumatoid arthritis, and bone marrow transplantation.
Treatment with EPO typically causes a rise in hemoglobin by about 1-3 g/dL in healthy humans over a period of weeks. When administered to anemic individuals, this treatment regimen often provides substantial increases in hemoglobin and red blood cell levels and leads to improvements in quality of life and prolonged survival. However, EPO is not uniformly effective, and many individuals are refractory to even high doses [see, e.g., Horl et al. (2000) Nephrol Dial Transplant 15, 43-50]. For example, over 50% of patients with cancer have an inadequate response to EPO, and approximately 10% with end-stage renal disease are hyporesponsive to EPO [see, e.g., Glaspy et al. (1997) J Clin Oncol 15, 1218-1234; Demetri et al. (1998) J Clin Oncol 16, 3412-3425]. Although the molecular mechanisms of resistance to EPO are as yet unclear, several factors, including inflammation, iron and vitamin deficiency, inadequate dialysis, aluminum toxicity, and hyperparathyroidism may predict a poor therapeutic response. In addition, recent evidence suggests that higher doses of EPO may be associated with an increased risk of cardiovascular morbidity, tumor growth, and mortality in some patient populations [see, e.g., Krapf et al. (2009) Clin J Am Soc Nephrol 4:470-480; Glaspy (2009) Annu Rev Med 60:181-192]. Therefore, it has been recommended that EPO-based therapeutic compounds (e.g., erythropoietin-stimulating agents, ESAs) be administered at the lowest dose that allows a patient to avoid red blood cell transfusions [see, e.g., Jelkmann et al. (2008) Crit Rev Oncol. Hematol 67:39-61].
Sideroblastic anemia, which occurs in both inherited and acquired forms, is characterized by the presence of “ring sideroblasts” in bone marrow. These distinctive red blood cell precursors (erythroblasts) can be identified by the presence of perinuclear siderotic granules, which are revealed by histologic staining with Prussian blue and are indicative of pathologic iron deposits in mitochondria [see, e.g., Mufti et al. (2008) Haematologica 93:1712-1717; Bottomley et al. (2014) Hematol Oncol Clin N Am 28:653-670]. Acquired sideroblastic anemia occurs most frequently in the context of myelodysplastic syndromes (MDS), a heterogeneous group of hematopoietic stem-cell disorders estimated to affect between 30,000 and 40,000 patients per year in the United States [Bejar et al. (2014) Blood 124:2793-2803]. These disorders are characterized by ineffective hematopoiesis, abnormal “dysplastic” cell morphology, and the potential for clonal evolution to acute myeloid leukemia. As discussed below, recent advances in the genetic basis of MDS have the potential to greatly improve its diagnosis and treatment.
There is high unmet need for effective therapies for MDS, sideroblastic anemia and complications of those disorders. Endogenous EPO levels are commonly elevated in subsets of patients with MDS, thus suggesting that EPO has diminished effectiveness in these patients. It has been estimated that fewer than 10% of patients with MDS respond favorably to EPO [Estey (2003) Curr Opin Hematol 10, 60-67], while a more recent meta-analysis found that EPO response rates range from 30% to 60% depending on the study [Moyo et al (2008) Ann Hematol 87:527-536]. Compared to other MDS patients, those with ring sideroblasts tend to be at substantially lower risk of developing acute myeloid leukemia and would therefore stand to benefit for an extended period from anti-anemia therapeutic agents that do not contribute to systemic iron burden and that instead help to reduce the iron overload frequently present in such patients [see, e.g., Temraz et al., 2014, Crit Rev Oncol Hematol 91:64-73].
Thus, it is an object of the present disclosure to provide methods treating patients with MDS and sideroblastic anemias with ActRII antagonists disclosed herein and, in particular, to guide selection of MDS patients that are most likely to show therapeutically beneficial increases in red blood cells, neutrophils, and other blood cells as a result of treatment.